The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients.

肌萎缩侧索硬化症 (ALS) 和额颞叶变性 (FTLD) 最显着的遗传原因是基因C9orf72的重复扩增。重要的是， C9orf72重复扩增的转录组学后果在很大程度上仍不清楚。在这里，我们使用短读长 RNA 测序 (RNAseq) 来分析小脑转录组，检测C9orf72重复扩增患者的变化。我们重点关注小脑，因为关键的C9orf72相关病理学在该神经解剖区域大量存在，但 TDP-43 病理学和神经元损失却很少。与之前的工作一致，当将进行扩增的患者与未进行C9orf72重复扩增的患者和对照受试者进行比较时，我们发现C9orf72基因的表达降低，同源盒基因升高。有趣的是，我们发现了超过 1000 个选择性剪​​接事件，其中 4 个发生在先前与 ALS 和/或 FTLD 相关的基因中。我们还发现，与未进行扩增的患者和对照患者相比，C9orf72患者的隐秘剪接有所增加。此外，我们证明了选定的 RNA 结合蛋白的表达水平与隐性剪接点包含相关。总体而言，本研究探讨了C9orf72患者死后组织中小脑（不被严重神经退行性疾病混淆的区域）是否存在广泛的转录组变化。